Catecholamines Flashcards

1
Q

What is the main excitatory and main inhbitory neurotransmitter?

(2 marks)

A

Glutamate is main excitatory

GABA is main inhibitory

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2
Q

What are the small molecule neurotransmitters?

A
  • Monoamines and acetylcholine
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3
Q

What do the monoamines consist of and what is the name of this group?

(4 marks)

A

Catecholamines:

  • Dopamine
  • Epinephrine (adrenaline)
  • Norephineprine (noradrenaline)
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4
Q

What do all the catecholamines have in common?

(2 marks)

A
  • All ave a catechol nucleus and amine group
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5
Q

What does the adrenal medulla secrete?

(2 marks)

A
  • Epiphrine and norepinephrine
  • Act as hormones in blood stream
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6
Q

How does the process of catecholamine synthesis begin?

(3 marks)

A
  • AA tyrosine ⇒ undegoes first hydroxylisation forming tyrosine hyroxylase (TH)…
    • TH used in dementia to measure function of dopaminergic neurons in basal ganglia
  • …and an aromatic amino acid decarboxylate (AADC) [precursor of DA] and is found in eurons that make DA
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7
Q

What is DOPA converted into?

(2 marks)

A
  • A catecholamine by dopamine ß hydroxylase (DBH)
  • And then into dopamine which is the direct precursor of norepinephrine
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8
Q

Where is PNMT and what is it?

A
  • Expressed in adrenal gland and can convert NE into EPI
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9
Q

At the DA and NE level what enzymes are expressed in their catabolic pathways?

A
  • MAO, COMT: produce different metabolites to be released in extracellular fluids throughout the brain
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10
Q

Excessive concentration of which molecules show that a patient has taken cocaine?

(2 marks)

A
  • HVA and VMA - produced from DA being catalysed by MAO/COMT
  • MHPG - produced by NE being catalysed from PNMT
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11
Q

Whatis the rate limiting enzyme in DA and NE synthesis?

A

Tyrosine Hydroxylase

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12
Q

How is the activity of TH regulated?

(2 marks)

A
  • High catecholamine levels will inhibit TH (negative feedback)
  • Rate of cell firing - when neurons fire at high rate TH is stimulated and catecholamine synthesis accelerates
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13
Q

How can catecholamine synthesis be increased?

A

Administration of pre-cursor i.e. L-DOPA (used to treat PD)

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14
Q

What does α-methyl-para-tyrosine (AMPT) do?

A

Blocks TH preventing the overall catecholamine synthesis

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15
Q

What happens to catecholamines after synthesis?

A

Packaged into a vesicle, and the vesicular monoamine transporter (VMAT) recognises the monoamines

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16
Q

What does the drug reserpine do to VMAT?

(2 marks)

A
  • Blocks it
  • And therefore increases accumulation of DA by causing paradoxical behaviourla effects
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17
Q

What can be seen when DA and NE are broken down?

A

Not in vesicle, so can see sedation and depression

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18
Q

How is catecholamine released?

A

By exocytosis when nerve impulse reaches terminal

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19
Q

What drugs cause release of catecholamines independently of cell firing?

(3 marks)

A
  • Amphetamine and Metaphetamine
    • in animal models see increased locomotor activity and stereotyped behaviours
    • Continuum of behavioural action stems from increasing stimulation of DA receptors in nucleus accumbens and striatum
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20
Q

What is catecholamine release inhibited by?

(6 marks)

A
  • Autoreceptors:
    • specific for each NT
    • largely located at pre-synaptic terminal ⇒ enhance opening voltage gated K+ channels
    • shortens duration of action potentials and reduces Ca2+ influx
    • and vesicle exocytosis aas membrane is hyperpolarised
  • Somatodendritic autoreceptors: inhibit NT release indirectly by reducing rate of firing of cell
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21
Q

What is Ki ?

(2 marks)

A
  • Dissociation constant
  • Equilibirum constant that specifically involves measure of prosperity of dissociation of a complex molecule into its subcomponents
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22
Q

What is Km ?

A

Substrate concentration at which reaction rate is half of its maximal value

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23
Q

What receptors do DA and NE contain?

(2 marks)

A
  • DA - D autoreceptors (1-5)
  • NE has α and ß autoreceptors
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24
Q

What do autoreceptor anatgonists do?

A

Enahnce rate of release of catecholamines

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25
Q

What do α2 agonists and anatagonists do after ingestion of opioids?

(2 marks)

A
  • α2 agonists: e.g. clonidine - used to treat symptoms of opioid withdrawal
  • α2 antagonists: e.g. yohimbine - blocks autoreceptors and increases noradrenergic cell firing and NE release. Provokes withdrawal symptoms and opioid craving
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26
Q

How is DA and NE reuptaken?

(3 marks)

A
  1. DA and NE removed from synaptic cleft to nerve terminal by specific transporter proteins
  2. Molecules re-packaged inot vesicles or broken down
  3. Transporter mediated uptake plays vital role in normal regulation of catecholamine activity
27
Q

What happens in mutant mice with no DA or NE transporters?

(2 marks)

A
  • No DA transporters - don’t respond to psychostimulants i.e. cocaine and amphetamines
  • No NE transporters - increased sensitivity to same drug
28
Q

Give some examples of drugs that block transport and their function.

(3 marks)

A
  • Tricycic antidepressants:
    • inhibit reuptake of both NE and serotonin
  • Reboxetine (edronax):
    • antidepressant and atomoxetine - drug used to treat ADHD
  • Cocaine:
    • inhibits reuptake of ALL monoamine transmitters: DA, NE & 5-HT
29
Q

How are DA and NE broken down?

(4 marks)

A

By enzymes COMT and MAO which produces:

  • DA metabolite - breakdown product is homovanillic acid
  • NE metabolites - MHPG in brain and vanillymandelic acid (VMA) in PNS

^^ metabolites enter CSF and blood stream and eliminated with rine

30
Q

What drugs inhibit breakdown enzymes?

(4 marks)

A
  • MAO inhibitors: i.e. phenolzine or tranylcypromine
    • Used to treat clinical depression
  • COMT inhibitors: i.e. entacapone and talcapone
    • enhance effectiveness of L-DOPA in treating PD by preventing breakdown of DOPA
31
Q

What is the classification system of cells for DA and NE?

(2 marks)

A
  • Cell groups A1-A7 are noradrenergic
  • Cell groups from A8 to A16 are dopaminergic
32
Q

What cell group does the nigorstiatal tract contain?

(3 marks)

A
  • Axons from A9 cell group in subtantia nigra - extends to caudate-putamen or striatum
  • Nigrostriatal tract is dopaminergic pathway and connects SNc to dorsal striatum
  • Critical in production of movemnt in basal ganglia motor loop
33
Q

Where is the A10 cell group located and what does it give rise to?

(3 marks)

A

In VTA and gives rise to 2 pathways:

  • Mesocorticocal dopamine pathway: from VTA to prefrontal cortex
  • Mesolimbic pathway:from VTA to different structures in limbic system
34
Q

Are the receptors for DA metabotropic or ionotropic?

A

Metabotropic and interact with G proteins and function via secondary messengers

35
Q

What receptor antagonists are almost all anti schizophrenic drugs?

A

D2 receptor antagonists

36
Q

What is the dopaminergic receptor famil consist of?

A

D1 and D5 are similar

D2, D3 , and D4 are seperate family

37
Q

Why is it more common to find cells that obly express either D1/D2 receptors and not both?

A

They act in opposite fashions - uncommon to find cell that expresses both

38
Q

How does a D1 receptor affect the production of cAMP?

A
  • D1 receptor is coupled to Gs and so it is positively coupled to adenyl cycalse and increases the production of cAMP
39
Q

How does the D2 receptor affect the production of cAMP?

A

Coupled to either Gi or Go and so is acting negatively on adenyl cyclase and therefore tends to reduce production of cAMP

40
Q

How do D2 receptors regulate membrane K+ channels?

A
  1. D2 receptor stimulation activates G protein that enahnces K+ channel opening and causes hyperpolarisation of cell membrane and decreases excitability and firing rate of cell
41
Q

What are different agonists for D autoreceptors and what do they do?

(4 marks)

A
  • SKF 38393 - for D1 receptors
  • Quinpirole activates D2 and D3 receptors
  • Apormophine agonist stimulates both D1 and D3 receptors:
    • causing behavioural activation simmilar to those seen in cocaine and amphetamines
42
Q

What do DA receptor antagonists do?

(3 marks)

A
  • Suppress exploratory and locomotor behaviour
  • At higher doses such durgs can result in catalepsy and lack of spontaneous movement
  • This is usually associated with D2 receptor blockers i.e. haloperidol
43
Q

What has been seen in DA transporter KO mice?

(2 marks)

A
  • Extremely hyperactive as DA cannot be removed from synaptic cleft
  • Mice tested in photocell apparatus - no. of photobeam breaks was recorded every 20 mins and all group showed gradual habituation
44
Q

What do KO of D1 and D2 receptor mice show?

(4 marks)

A
  • D1 KO show deficits in cognitive tasks
  • D2 KO show impairment in spontaneous movement, co-ordination and posture control
  • Double KO of both D1 and 2 show reduced or no increase in locomotion
  • Double KO of both D1 and D2 receptor genes leads to fatality during 2nd or 3rd week of life
45
Q

What do D4 receptor mice KO show?

A

Mice are hypersensitive to metamphetamines and cocaine

46
Q

How can rodents develop behavioural sypersensitivity?

A

From the adminstration of a D2 receptor antagonist i.e haloperidal - given on a long term basis

47
Q

What are the central and peripheral components of the noradrenergic system?

(2 marks)

A
  • Central: cell bodies are in the brainstem and ascending fibres go to forebrain structures
  • Peripheral: part of sympathetic nervous system
48
Q

Where are NE neurons located in the brain?

(3 marks)

A
  • Found in pons and medulla
  • Locus coerulus (LC) in pons: dense collection of NE neurons corresponding to A6 cell group
  • Fibres extend to nearly all areas of forebrain and cerebellum and spinal cord
49
Q

How can NE reach organs in the body?

(2 marks)

A
  • Released from sympathetic noradrenergic neurons at synapse - like contacts with cardiac cells
  • Released from adrenal glands and travel in bloodstream to heart
50
Q

Are adrenergic receptors metabotropic or ionotropic? What are the existing subtypes?

(4 marks)

A
  • Metabotropic
  • subtypes:
    • α1/2 receptors and ß receptors
    • α2 receptors - reduce synthesis of cAMP
    • α1 receptors - operate via phosphoinositide secondary messenger system
    • ß1/2 - adrenoreceptors stimulate adenyl cyclase and enhance synthesis of cAMP
51
Q

What is the central noradrenergic system involved in?

(2 marks)

A

Arousal, cognition, consolidating memories of emotional experiences

LC projects to prefrontal cortex which plays a role in attention and working memory

52
Q

What happens after the activation of α1/2 receptors in the prefrontal cortex?

(2 marks)

A
  • α1 receptor activation - deleterious affect on cognitive function
  • α2 receptor activation - activated by using selective agonists i.e. clonidine - enhances working memory
53
Q

How does NE faciliate PFC functon and cognitive tasks in normal conditions?

A

Activates adrenoreceptors there

54
Q

Which α receptor does NE have a lower affinity for in the prefrontal cortex?

55
Q

What is increased NE associated with?

A

Stress or increase in α1 receptor activation - can lead to cognitive impairment

56
Q

Why do odents show increased time awake after adminstration of either α1 or ß-adrenergic agonists?

(2 marks)

A
  • LC neurons fire more rapidly during waking than asleep
  • Noradrenergic pathways from LC to medial septal and medial preoptic areas are involved in wakefulness
57
Q

What molecules are impliacted in consolidation of emotional memory and how is memory consolidation evaluated?

A
  • NE, EPI and glucocorticoid hormones
  • Measured using ‘one-trial passive avoidance learning paradigm’
58
Q

Why are EPI modulates used in treatment of non-psychiatric conditions?

A

Due to widespread distribution of adrenergic receptors in peripheral organs

59
Q

What is used to treat asthma?

(also in COD)

A
  • ß2 agonists e.g. albutenol in an inhaler
60
Q

What is used to treat hypertension?

(4 marks)

A
  • α1 - antagonist prazosin and ß - anatognist propanolol
  • Prazosin blocks α1-receptors that cause blood vessel constriction
  • Propanolol blocks ß-receptors in the heart reducing its contractile force
  • ß1 is main subtype in the heart and its seleciev antagonists i.e. metoprodol have fewer side effects
61
Q

What are ß antagonists used to treat?

A

Anxiety - reduce phsyical symptoms e.g palpitations

62
Q

What are α2 agonists used to treat?

A
  • Hypertension - as inhibit activity of sympathetic nervous system while stimulating parasympthatetic NS
63
Q

What is dexmedetomidine?

(2 marks)

A
  • α2 agonist
  • When combined with sedative i.e. anxiolytic and analgesic has pain reducing and anti anxiety effects